PROJECT SUMMARY My career goal is to become a leading epidemiologist investigating the causes of multiple sclerosis (MS) onset and progression. MS is a complex disease involving both genetic and environmental factors, and I believe it is not sufficient to study single exposures or siloed genetic, environmental, or social causes. My long-term research will reflect this complexity by incorporating genetic, social, and environmental factors into models of MS causation and progression and specifically emphasize gene-environment interactions. One environmental factor that has been implicated in the development and exacerbation of MS in adults is stress, but it is unclear whether stress in childhood and its interaction with genes affects MS risk or clinical phenotypes. The objective of this proposed research project is to investigate whether childhood stressful life events, and their interaction with genetic variants, contribute to risk of MS and long-term physical disability and cognitive impairment among MS patients. A critical barrier to making progress in this area of MS research has been the inability to collect high quality clinical outcomes data. To address this barrier, we will use the new, validated web-based tool, ?ICLIC-MS? or Internet Interface for Clinical and Longitudinal Information Collection for MS, to longitudinally collect MS-validated measures of cognitive function and physical disability. Aim 1: Test for gene-environment interaction between genetic risk variants and childhood stressful life events on MS risk. We will conduct a case-control study using 13,500 participants from the Kaiser Permanente Northern California (KPNC) MS Research Program. Aim 2: Estimate the association between childhood stressful life events and physical disability among MS patients overall and across genetic susceptibilities. Aim 3: Estimate the association between childhood stressful life events and cognition among individuals with MS overall and across genetic susceptibilities. We will estimate the associations in Aims 2 and 3 among >1,000 KPNC MS cases cross- sectionally and longitudinally over three years. By establishing whether childhood stress interacts with genetic variants to affect MS risk, cognition, or physical disability, we might be able to target at-risk populations for psychosocial and clinical interventions, potentially reducing risk of MS, limiting progression, and improving quality of life for individuals living with MS. This research project and associated training plan were developed in collaboration with my sponsor, Dr. Lisa Barcellos, and co-sponsors, Drs. Emmanuelle Waubant and William Jagust. The training plan emphasizes scientific productivity and building a strong knowledge of epidemiologic and biostatistical methods, the social and biological basis of stress, and MS processes. As a student at UC Berkeley, I am well supported by an institution that values rigorous scientific research and have access to many research and professional resources. Ultimately, the proposed research and achievement of the goals outlined in the training plan will train me to become a multidisciplinary, independent investigator and facilitate my transition into a post-doctoral position and early-investigator faculty or non-profit research position.